N-benzyl emetine



United States Patent 0 3 Claims. or. 260-288) This application is adivision of Serial No. 111,908, now issued on October 1, 1963, as PatentNo. 3,105,835.

This invention concerns novel intermediates for use in the chemicalsynthesis of emetine and its analogues, and to processes for thepreparation of such analogues.

The alkaloid emetine is widely used, particularly in Asia and Africa, tocombat amoebic dysentery. A number of synthetic substances have beensuggested as substitutes for this naturally occurring compound but nonehas been found to be more satisfactory in practice. In consequence,there exists a demand for a synthetic process leading to emetine whichis capable of producing the alkaloid more cheaply than by the presentextraction from the natural source. Several synthetic processes have, infact, been proposed but so far as we are aware, none has provedsatisfactory for commercial purposes.

In copending U.S. Patent application Serial No. 40,200, now US. PatentNo. 3,121,720, we have described compounds and processes of use, interalia, in :the synthesis of emetine and its analogues, one of whichprocesses comprising the reaction of a compounds having the skeletal(where groups R represent hydrogen atoms or organic groups which may bethe same or dilferent) with a substance able to introduce onto theN-atoms a side chain which can condense with the central carbonyl groupto form the -membered C ring present in emetine. Two such side chainswere exemplified, namely and COCH R (where R and R are organic groups).The resulting compound having two identical side chains is thensubjected to ring closure, whereupon one only of the chains condenseswith the central carbonyl group while the other remains unreacted toprotect the N-atorn to which it is attached in later stages of thesynthesis.

3,234,227 Patented F ch. 8, 1966 We have now found that a compoundhaving the skeletal structure (where R represents an inert group ashereinafter defined and R has the above meaning) is in some respectseven more convenient as an intermediate in the synthesis of emetine thanis the symmetrical compound of structure I above. Where emetine itselfis required the group R should be removable without affecting theremainder of the molecule and for this purpose an arylmethyl group,preferably a benzyl group is especially suitable.

If, however, the desired final product is an N-substituted emetineanalogue, the group R may be conveniently either the desiredN-substituent or a group which can be converted thereto. Such groupingsinclude alkyl, alkenyl and aralkyl groups, which may if desired carrysubstitutents inert in the various reactions to be outlined below,

The compound II, in order to synthesise emetine or one of its analogues,may then be substituted at the secondary amino group with a side chainwhich is able to condense with the central carbonyl group, in particulara group CH CH COR where R represents an organic group, for example analkyl, aryl, aralkyl group etc.

The grou -CH CH COR may conveniently be introduced by reacting compoundII with a vinyl ketone CH =CHCOR The reaction proceeds in the absence ofa catalyst in a solvent for the reactants.

The cyclisation of the appropriately N-substituted derivatives ofcompounds of basic structure II may take place under the conditionsgenerally used for condensation of a carbonyl group with a reactivehydrogen atom.

Where the side chain is CH CH COR the cyclisation is preferably carriedout in the presence of a basic catalyst. The cyclised product is analcohol of the general formula solvent e.g. a lower alcohol,tetrahydrofuran, dioxan etc; sodium hydride or sodamide suspended in asuitable solvent e.g. benzene, toluene etc.; but the preferred method isan alkali metal alkoxide in the appropriate alcohol advantageously inthe presence of an added inert solvent such as a hydrocarbon solvente.g. benzene, toluene etc. or a chlorinated hydrocarbon solvent e.g.chloroform, methylene chloride etc.

The normal dehydrating agents can be used for the dehydration step e.g.phosphorus oxyohloride, thionyl chloride or trifluoroacetic anhydride,in neutral solvents, e.g., benzene etc., or base e.g. pyridine. Thepreferred method is the use of concentrated (11 N) hydrochloric acid or11 N sulphuric acid at elevated temperature, usually about 100 C. Loweracid concentrations are less effective. E

The dehydrated product possesses the formula (III-1) (where R, R and Rhave the above given meanings) although some material may be formed inwhich the unsaturation in the C-ring is difierently placed.

Where compounds of skeletal Formula III-d are to be converted intoemetine or its analogues, the C-ring unsaturation may be reduced e.g. byreduction with a metal/ amine or, preferably, a metal/ ammonia reducingsystem. The metal is advantageously an alkali metal or alkaline earthmetal, e.g. sodium, potassium, calcium etc. lithium being, however,preferred. The compound to be reduced may be added to the ammonia oramine solution of the metal in an inert solvent e.g. an ether such asdiet-hyl ether or tetrahydrofuran or a hydrocarbon solvent such asbenzene or toluene.

Such reduction generally leads to compounds in which the hydrogen atomintroduced at the 2-posi-ti0n is in the arather than theB-configuration. We have found that the rat-isomer can be converted intothe B-isomer, for example by equilibration under strong enolisingconditions, e.g. in the presence of concentrated aqueous acid or organicor inorganic base. The acid may, for example, be a mineral acid such ashydrochloric, sulphuric or phosphoric acid While the base may be, forexample, an alkali metal hydroxide such as sodium or potassiumhydroxide, or a tertiary nitrogen base such as triethylamine.

We have also found that it is the ,fi-isomer which leads to emetine andits analogues and it is necessary to efiect the conversion describedabove where these compounds are required. Where conditions in anysubsequent reactions-steps are strong enolising conditions, however, theseparate step of conversion may not be required.

Where compounds are required in which the 3-position side chain is alkylrather than acyl, the carbonyl group of the acyl group may 'be reduced,e.g. by reaction with hydrazine and alkali (Wolflf-Kishner reaction) orby the action or a met-al/ acid reducing system (Clemmensen reduction).An alternative method is to convert the carbonyl group into a thioketalgroup, for example by reaction with ethane dithiol, and to reduce this[for example with Raney nickel or Raney iron, cobalt etc. or withhydrazine and alkali It should be noted that Wolfi- Kishner reactionconditions are often vigorous enough to hydrolyse methoxyl or otherether groups which may be present in the aromatic rings. Such groups maybe restored, however, by reaction with appropriate etherify ing agents.

Compound II also of use in an alternative route by' which emetine may beobtained. In this method group CO.CH --R is attached at the NH group ofcompound- II, e.g. by reaction with an anhydride or acid halide, theresulting side chain then being cyclised, preferably in thepresence of abasic catalyst, for example potassium ter-- tiary butoxide. In thiscase, however, the predominant product is a compound of the formula(III-2) (where R, R and R have the above given meanings) or the'y:6-unsaturated isomer thereof.

Compound III-2 may then be converted to closer analogues of emetine byreduction of the C-ring unsaturation, and reduction of the cyclic amidegrouping.

It will be seen that the group R must be one which will remainsubstantially inert in the cyclisation and dehydration and the terminert substituent is used in that sense herein. The nature of R ispreferably also such that it remains unaffected in such further steps asWolfi-Kishner reduction and metal/ ammonia reduction. Preferably Rshould also be removable from the N-atom to which it is attached withoutdisruption of the molecule (since the intermediate II will then be ofuse in the synthesis or emetine or analogues possessing a free NHgrouping) except where it is a substituent of a nature desired in thefinal molecule.

The compound II may be substituted in the 3, 4, 5, 6, 7 and/or 8position of both the isoquinoline rings by a wide variety of groupingsand may thus be used to prepare a large number of emetine analogues. Thesubstituents should of course be inert in the attachment of the sidechain to the secondary nitrogen atom and the subsequent cyclisationreaction and will be chosen having regard to the nature of thesubstituent or substituents: present in the alkaloid or other compoundit is desired to synthesise. Suitable substituents are thus forexamplealkyl, aralkyl, aryl, alkoxy, aralkoxy, aryloxy, or tertiaryamino groups, e.g. methyl, ethyl, propyl, isopropyl, butyl, amyl,benzyl, phenyl, methoxy, ethoxy, propoxy, butoxy, benzyloxy, phenoxy, ordi-alkylamino groups. Substituents may also occupy more than oneposition, as in methylene dioxy groups. In order to prepare emetineitself the 6, 7, 6 and 7' positions only of compound II should carrymethoxy groups and the symbols R should represent hydrogen atoms.

Com-pound II may be prepared in any convenient way. A number of methodsare given herein and form part of the present invention.

(1) A compound having the structure may be reacted with an isoquinolinepseudo base having the structure OH (V) (where R and R have the meaningsgiven above). Preferably the groups R are either all hydrogen atoms orone of the groups R attached to the terminal carbon is a carboxyl groupwhile the other three groups R are hydrogen atoms. In the last-mentionedcase, the carboxyl group splits oil? during the condensation.

Where all the groups R are hydrogen atoms the condensation isadvantageously carried out in the presence of an acid or, preferably, abasic catalyst. We prefer to efiect the reaction at room temperature ina solvent, such as an alkanol and one suitable system is ethanolcontaining anhydrous sodium carbonate. Other bases are suitable,however, for example sodium ethoxide, sodium hydroxide, trimethylarnineor piperidine but generally give lower yields.

Where one of the terminal groups R is a carboxyl group, however, theterminal hydrogen atom is activated and the condensation will generallytake place in the absence of a catalyst. In view of the instability of,B-keto carboxylic acids, the reaction is preferably carried out at roomtemperature or below. The reaction solvent is preferably a loweralkanol, with or without water present, but other polar solvents such asketones e.g. acetone, MEK etc. ethers such as tetrahydrofuran, dioxan,etc. substituted amides such as dimethylformamide etc. may also be usedin the presence or absence of water. Acid or basic catalysts may bepresent but are not generally required and may reduce rather thanincrease the yield.

Compound IV may be prepared by reacting a compound of structure with acompound of general formula CHR COCHR (where R has the meanings givenabove). Preferred compounds of Formula VII are acetone, acetoacetic acidand acetone dicarboxylic acid. Care should be taken that suificientcompound VII is present in the reaction mixture to ensure that a minimalquantity of compound I is formed.

Where all the groups R of compound IV are to be hydrogen atoms, compoundVII is conveniently acetone or acetoacetic acid. This reaction may becarried out with an approximately 1:1 mixture of reactants in a basicsolution such as pyridine in the case of acetone or merely in water inthe case of acetoacetic acid.

Where one of the terminal groups R of compound 1V is a carboxyl group,compound VII is conveniently acetone dicarboxylic acid.

The ratio of reactants is advantageously about 1:1 anc the reaction isconveniently carried out in aqueous solu tion in the presence or absenceof polar organic solvents e.g. lower alcohols, dioxan etc. The preferredreaction medium comprises aqueous methanol used at or below roomtemperature.

Compound IV may also be prepared by reacting compound V with compoundVII followed by removal of the group R although, in general, this isless convenient.

6 Compound V may be conveniently prepared by quater nising compound VIto form a compound of the structure (where R has the above meaning and Xis an anion) which may then be reacted with alkali, preferably in thecold, to form the pseudo base.

(2) A compound having the structure (VIII) (Where R and R have themeanings given above), may be reacted with compound VI shown above undersubstantially the same conditions as are described for the reaction ofcompounds VI and VII above. Preferably symbols R all represent hydrogenatoms or three represent hydrogen atoms while one of the two groupsattached to the terminal carbon atom is a carboxyl group.

Compound VIII may be prepared by reacting compound V with compound VII,under such conditions that only one molecule of V condenses with eachmolecule of VII. The conditions for carrying out the condensation aresimilar to those described in (1) above.

In all the reactions described above, the compounds represented by theskeletal structures shown may be substituted with the groupings desiredin compound II. In particular, when close analogues of emetine are to bethe final products, the 6 and 7 position of the isoquinoline moietiesshould carry methoxy groups. Most of the compounds having structures II,III, IV, V and VIII are new compounds and such new compounds form partof the present invention.

When the groups R are all identical, compound II possesses twoasymmetric carbon atoms, namely at positions I and 1, and it thereforeexists in the form of two pairs of enantiomorphs. In the syntheticprocesses described, all four isomers of compound II are formed andsince only one of these leads to natural emetine or its analogues in thesame stereoisomeric series, resolution is required at some stage in theoverall synthesis. We have found that in the case where the groups R areall hydrogen and R is benzyl, and the 6, 7, 6' and 7' positions carrymethoxy groups the racemates may be separated by solubility differencesof the salts. One of the racemates, which we have termed isomer A, canbe precipitated as its hydrochloride from methanol with ethanolichydrogen chloride, while the other, isomer B, remains in solution andmay be isolated as a sparingly soluble hydrobromide. Resolution of theseparated racemates may be efiected at this stage or later in thesynthesis. We have shown that the present isomer B is in the samestereochemical series as natural emetine.

In order that the invention may be Well understood we give the followingexamples by way of illustration only. All temperatures in C.

EXAMPLE 1 (a) Z-benzyZ-3,4-dihydr0-6,7-dz'meth0xyisoquinolz'nium bromide3,4-dihydro-6,7-dimethoxyisoquinoline (9.0 g.) in sodium-dried benzene(70 ml.) was treated with redistilled benzyl bromide (6.0 ml.; 1.05mols) whereupon .a partly solid gum separated. After 1 hr., the producthad soliditied to a yellow powder (13.4 g., M.P. 17882) which separatedfrom ethanol in pale yellow tablets (12.5 g.;

7 crystallisation from ethanol gave the analytical specimen, M.P.198-200". Found: C, 60.3; H, 5.5; N, 3.8; Br, 21.9%. clgHgoozNBrrequires C, 59.7; H, 5.5; N, 3.9; Br, 22.1%.

(b) Z-benzy l-l ,2,3,4-tetrahydro-1 -hydrxy-6,7- dime thoxyiso quinoline (1) A solution of 2-benzyl-3,4-dihydro-6,7-dimethoxyisoquinoliniumbromide (50 g.) in water (1800 ml.) was cooled to 6 and aqueous sodiumhydroxide (280 ml., 0.6 N) was added dropwise with stirring over 3 hr.The product was filtered, washed with water and dried in vacuo giving apale yellow powder (42 g.; 100%), M.P. l078. Crystallisation frombenzene-petroleum ether (4060) gave the analytical specimen, M.P. 111".Found: C, 72.0; H, 7.1; N, 5.0%. C H O N requires C, 72.2; H, 711; N,4.7%.

(2) 2-benzyl-3,4-dihydro-6,7-dimethoxyisoquinolinum bromide (15.6 g.)was dissolved in aqueous trimethylamine (25% w./v.) (100 mls.) to give aclear yellow solution. When the solution was scratched and allowed tostand at room temperature a fine white precipitate was obtained. Afterone hour this was removed by filtration, washed well with water anddried in vacuo at room temperature. Wt.=11.58 g. (92%), M.P. 112-115 C.(d).

(c) 6:7-dimeIhOxy-l,2,3,4-tetrahg dro-isoquinoll-yl-acetoacetic acid6,7-dimethoxy-3,4-dihydroisoquinoline (24 g.) was dissolved in methanol(48 ml.) and water (192 ml.). The mixture was cooled to below roomtemperature in cold water, and a solution of acetone dicarboxylic acid(18.5 g.) in water (48 ml.) added. After 2 /2 hr. with continuouscooling and occasional shaking the fine white solid was filtered, washedwith water, industrial methylated spirits and finally with ether. Afterdrying in vacuo at room temperature, the product weighed 19.2 g., M.P.101-3" (decomp.). (Found: C, 60.92; H, 6.56; N, 4.57. C H O N requiresC, 61.42; H, 6.53; N, 4.78%.)

(d) 2-benzyl-6,7-dimethoxy 1(6,7-dimethoxy-1',2,3',4-tetrahydro-isoquin'ol 1-yl-acetonyl) 1,2,3,4-tetrahydroisoquinoline,(isomers A and B) 1) 2-benzyl-1,2,3,4-te-t.rahydro1-hydroxy-6,7-dimethoxyisoquinoline (10.8 g.) was dissolved inindustrial methylated spirits (54 ml.) at room temperature.6,7-dimethoxy1,2,3,4 tetrahyroisoquinol-l-yl-acetoacetic acid (9.2 g.)was added and the mixture allowed to stand with occasional shaking. Aslow effervescence occurred and the suspension gradually dissolved.After 1 /2 hrs. a little undissolved solid was removed by filtration,and the solution treated with saturated ethanolic hydrogen chloride topH 1.0 with cooling. After standing overnight in the refrigerator theresultant solid was filtered ofii, washed with industrial methylatedspirits, and dried in vacuo at room temperature to give thehydrochloride of isomer A. Wt.=6.6 g. (30%), M.P. 145-8 (d.). (Found: C,59.80; H, 6.79; N, 3.96; Cl, 10.89

requires C, 60.09 H, 6.93; N, 4.38; Cl, 11.09%.)

Treatment of the filtrate with ether gave an orange yellow gum, whichwas separated from solvent by decantation and drying in vacuo. This wasdissolved in water (200 ml.) and excess ammonium bromide addedportionwise with scratching. The pale yellow precipitate was filteredoff, treated with industrial methylated spirits and allowed to stand inthe refrigerator overnight. The product was filtered, washed with thesame solvent followed by ether and dried in vacuo to give thehydrobromide of isomer B. Wt.=4.1 g., M.P. 1525 (d.). Found: C, 54.91;H, 6.2; N, 4.12; Br, 22.52.

C32H3 05N2 ZI'IBI requires C, 54.79; H, 5.89; N, 4.0; Br, 22.78%).

(2) 1-(1,2,3,4 tetrahydro-6,7 dimethoxyisoquinol-lyl) acetone (1.2 g.)prepared as described in US. Patent application Serial No. 40,200, nowUS. Patent No. 3,121,720, and 2-benzyl-1,2,3,4-tetrahydro-1-hydroxy-6,7-dimethoxyisoquinoline (1.26 g.) were dissolved in ethanol (9.5 ml.)containing anhydrous sodium carbonate (0.025 g.), and the solution wasallowed to stand at room temperature for 12 hours then in therefrigerator for 2 days. Water was then added and the mixture wasextracted with benzene. The benzene extract was washed with water, dried(MgSO and evaporated to dryness. The resulting oil (2.29 g.) wasdissolved in industrial methylated spirits (25 ml.), and ethanolichydrogen chloride was added to pH 1. The solution was cooled, andcrystals (0.53 g., 18%), M.P. of the hydrochloride of isomer A weredeposited. Starting material (0.12 g.) was obtained from the motherliquor.

In other experiments, sodium hydroxide, sodium ethoxide, trimethylamine,or piperidine were the catalysts used. The yields varied from 13 to 26%.

EXAMPLE 2 2-benzyl-1-(6',7' dimethoxy-2'-(3-keto but-1-yl)-1,2',3,

4'-tetrahydro isoquinol-l-acetonyl)-6,7 dimethoxy-J,2,3,4-tetrahydro-isoquinoline (A series) The hydrochloride is isomer Aprepared in Example 1(b) (3 g.) was dissolved in water and the solutionbrought to pH 10 with aqueous sodium carbonate solution. The mixture wasextracted with benzene (1x20 ml., 2x10 1111.). The first two extractswere combined and washed with water (3X30 ml.) the washes beingback-extracted with the third benzene extract. The combined benzenelayers after drying (MgSO had a volume of 45 mls.

Methyl vinyl ketone (0.825 ml.) was added and the mixture allowed tostand overnight at room temperature in vacuo to give a pale gummyresidue. Addition of ether, followed by removal of the solvent in vacuogave a pale foam which was not characterised further but was used forthe next stage. Wt.=2.78 g.

The process was repeated using the hydrochloride of isomer B prepared inExample 1 and the product used Without purification in the next stage.

EXAMPLE 3 3-acetyl-2-hydroxy-9,10 dimethoxy-Z(2'-benzyl-6',7-dimethoxy-l ',2,3,4-tetrahydro isoquinol-l '-yl-methyl)-1,2,3,4,6,7 hexahydro-llb[H]benz0[a] quinolizine hydrochloride (Aseries) The A series product from the preceding example (2.78 g.) wasdissolved in benzene (70 mls.) and sodium methoxide (0.29 g.) inmethanol (5.5 mls.) added with mechanical stirring at room temperature.After 15 minutes an equal volume of water was added. The layers wereseparated and the aqueous phase extracted with benzene (2X25 mls.). Thefirst two extracts were combined and washed with water (3X50 mls.) thewashes being back extracted with the third benzene extract. The combineddried (MgSO benzene layers were evaporated to dryness in vacuo at roomtemperature and ether (ca. 50 mls.) added. After ca. 15 mins. a whitesolid (66 mg.) separated and was removed by filtration.

The mother liquors were evaporated to dryness and the residue dissolvedin industrial methylated spirits (20 mls.) Ethanolic hydrogen chloridewas added, with cooling to pH 1. The pale yellow solution was scratchedvigorously and after a few minutes a fine white solid was deposited. Thesuspension was allowed to stand in the refrigerator overnight when thesolid was harvested, washed with industrial methylated spirits and driedat room temperature in vacuo to give the desired hydrochloride. Wt.=1.93g. (55% from starting hydrochloride), M.P. 198 C. (d.). Found: C, 61.24;H, 7.15; N, 3.52;

9 Cl, C3 H O N2Ci '2H2O requires C, H, 7.10; N, 3.95; 01, 9.99.

The free base had M.P. 148-9". (Found: C, 71.94; H, 7.25; N, 4.4; C H ON requires C, 71.97; H, 7.38; N, 4.66%.)

The process was repeated with the B series product of Example 3 and theproduct was isolated as the hydrochloride, M.P. 187-9 (Found: C, 62.61;H, 7.39; N, 3.76; Cl, 10.0. C H., O N Cl -H O requires C, 62.51; H, 7.0;N, 4.05; CI, 10.2%.) The free base had M.P. 178-9. (Found: C, 71.93; H,7.61; N, 4.46; C H O N requires C, 71.97; H, 7.38; N, 4.66%.)

EXAMPLE 4 3 acetyl- 9,10-dimeth0xy-2 (2'-benzyI-6,7-dime.h0xy-l 2',3,4tetrahydroisoquinol-l'-yl-methyl) -1,4,6,7-tetrahydro 11 b [H]-benzo[a]-quinolizine The A series hydrochloride prepared in Example 3 (1 g.) wasdissolved in water and adjusted to pH 10 with aqueous sodium carbonate.The mixture was extracted with benzene (3 x 10 mls.). The first twoextracts were combined and washed with water (3 x 25 mls.), the washesbeing back extracted with the third benzene extract. The solvent wasremoved from the combined, dried (MgSO benzene extracts and the residualgum heated on the steam bath with 11 N sulphuric acid mls.) undernitrogen for 2 /2 hours. The pale yellow solution was cooled andadjusted with sodium hydroxide to pH 6, and then with aqueous sodiumcarbonate to pH 10. Before neutralisation had been achieved an orangegum separated which did not dissolve either in excess alkali or inbenzene (2O mls.) which was now added. The solvent layers were decantedand the gum dissolved in methanol, diluted with water, and poured intothe water/benzene mixture when it was not re-precipitated. The layerswere separated and the aqueous phase extracted with benzene (2 x 20rnls.). The benzene layers were washed with water (3 x mls.) in theusual way and dried (MgSO Removal of the benzene in vacuo at roomtemperature, followed by evaporation of the residue with ether gave apale pink foam. Addition of ether and scratching gave a pale crystallinesolid. This was filtered off, washed with ether and dried in vacuo atroom temperature to give the desired product. Wt.=0.44 g. (53 g.), M.P.145-6 C.

Found: C, H, N, C36H42O51/2H2O requires C, 73.07; H, 7.32; N, 4.74% LR.carbonyl stretching frequency 1678 cmf The process was repeated usingthe B series isomer prepared in Example 3 and the product was isolatedas the free base, M.P. 132-1335". Found: C, 73.96; H, 6.97; N, 4.6. C HO N requires C, 74,19; H, 7.27; N, 4.81%.

EXAMPLE 5 2-benzyl-3,4-dihydr0-6,7-dimethoxyisoquinolinium bromide3,4-dihydro-6,7-dimethoxyisoquinoline (50 g.) was dissolved inindustrial methylated spirits (250 ml.) and benzyl bromide (33.5 ml.)added portionwise with cooling at room temperature. The mixture wasseeded and scratched, and after 1 /2 hr., the quaternary bromide wasfiltered oii, washed with a little industrial methylated spirits anddried in vacuo at room temperature. Wt.=43.7 g., M.P. l92-5. A secondcrop (9.67 g.) was obtained by the addition of petroleum ether (B.P.60-80") to the mother liquors.

EXAMPLE 6 3 acetyl-J,2,3,4,6,7-hexahydr0-9,IO-dimethOxy-Z-(Z-benzyl1,2,3,4 s'ezrahydro6,7-dimetlzoxyisoquinol-I-ylmetlzyl)-1Ib[H]benz0[a]quin0lizine Aseries.-Calcium metal (1.6 g.) was added to liquid ammonia (300 m1.) andthe mixture stirred under reflux for 30 min. The conjugated ketone (Aseries) obtained in Example 3 (10 g.) in a mixture of benzene (50 ml.)and ether ml.) was added over about 3 min. to the reaction mixture withvigorous stirring. After 10 mins. excess metal was destroyed by theaddition of acetone, and the ammonia removed by evaporation. Water (100ml.) and benzene (50 ml.) were added and the mixture filtered throughkieselguhr. The layers were separated, and the aqueous phase extractedwith further portions of benzene (2 x 50 ml.). The benzene extracts wereWashed with water, the solvent removed in vacuo, and the residuetriturated with ether (30 ml.). The crude solid obtained was dissolvedin 11 N-sulphuric acid and heated in the steam bath under nitrogen for 2hr. After cooling, and basification with potassium carbonate, themixture was extracted with benzene, the extracts being washed with waterin the usual way. Distillation of the solvent and crystallisation of theresidue from ether gave the desired saturated ketone, M.P. 107-109 C.(Found: C, 73.7; H, 7.8; N, 4.7. C H O N requires C, 73.9; H, 7.6; N,4.8%.) The hydrochloride gave prisms from methanolether, M.P. 206-208 C.(d.). Found: C, 62.0; H, 7.3; N, 3.9; Cl, 9.7. C H O N -2HCl'2H Orequires C, 62.3; H, 7.3; N, 4.0; Cl, 10.2%.)

B series.The conjugated ketone (B series) obtained in Example 3 (2.57g.) in dry tetrahydrofuran ml.) was added to a stirred solution oflithium (0.315 g.) in liquid ammonia (approx. 400 ml.) and the mixturestirred at the boiling point for 30 min. The excess metal was destroyedby the addition of acetone, and the crude product isolated with benzeneas in the previous example. The crude product, after partialpurification on a Florisil column, was heated on the steam bathovernight in 2 N-hydrochloric acid to effect equilibration, and theprodnot isolated as before with benzene. Crystallisation from ether gavethe desired saturated ketone, M.P. 1425-144 C. (Found: C, 72.5; H, 7.6;N, 4.4. C H O N -2H O requires C, 72.8; H, 7.6; N, 4.7%.)

The hydriodide gave pale yellow crystals from Water. (Found: C, 49.5; H,6.1; N, 2.9; I, 28.8.

' (3. (Found: c, 52.25; H, 6.2; 01, 8.2.

C36H44O5N2 requires C, 52.6; H, 6.1; Cl, 8.6%.)

EXAMPLE 6 Preparation of thiokemls (A series) The saturated ketone (Aseries) obtained in Example 5 (0.9 g.) was suspended in anhydrousmethanol (18 ml.) and saturated with dry hydrogen chloride at 0 C.Ethane dithiol (0.9 ml.) was added, and the passage of gas continued fora further 2 hr. at 0 C. After standing overnight at room temperature,the methanol was removed by distillation in vacuo, water and benzeneadded, and the mixture neutralised to pH 10 with aqueous sodiumcarbonate. The free base was isolated with benzene in the usual way, andthen isolated as the hydrochloride by treatment with 2 N-hydrochloricacid. After crystallisation from alcohol, the hydrochloride had M.P.205208 C. (Found: C, 57.1; H, 7.2; N, 3.3; Cl, 8.9; S, 8.2.

C38H4304N2S2 3 requires C, 57.3; H, 7.2; N, 3.5; Ci, 8.9; S, 8.05%.)

T hioketal (B series) The saturated ketone (B series) obtained inExample 5 was converted into the thioketal by the above procedure. Theproduct was isolated as the hydrobromide from ethanol-ether, M.P. 212 C.(Found: C, 52.35; H, 6.3;

11 N, S, Bl, C33H48O4N2S2HBI'3HZO requires C, 52.1; H, 6.4; N, 3.2; S,7.3; Br, 18.2%.)

EXAMPLE 7 Preparation of N-benzylisoemetine The thioketal (A series)obtained in Example 6 (0.41 g.) in xylene (30 ml.) was refluxed withvigorous stirring with Raney nickel '(W4; approx. 6 g.) for 16 hr. Thenickel was filtered from the cooled reaction mixture, washed withbenzene, and the combined filtrate and washings washed with 2 N-sodiumhydroxide and Water. Removal of the solvent gave a crude foam whosesolution in 2 N-hydrochloric acid, on treatment with excess aqueouspotassium iodide solution, gave N-benzylisoemetine hydroiodide, M.P.198202 C.

EXAMPLE 8 Preparation of N-benzyleme-tine The thioketal (B series)obtained in Example 6 (0.85 g.) was heated in refluxing xylene (50 ml.)with Raney nickel (W4; 6.0 g.) for 24 hours. The crude free base,isolated as before, was purified by chromatography on alumina (25 g.;grade H; ethyl acetate-benzene) to give (+)N-benzy1emetine as a froth.

The hydrobromide, crystallised from ethanol, had M.P. 211213 C. ((1.).(Found: C, 55.3; H, 6.7; N, 3.6; Br, 19.7. C H N O -2HBr-3H O requiresC, 55.0; H, 6.9; N, 3.6; Br, 20.3%.)

EXAMPLE 9 Preparation of isoemetine N-benzylisoemetine obtained inExample 6 (0.5 g.) was dissolved in water (50 ml.) containing 2N-hydrochloric acid (10 ml.) and added to a pre-reduced suspension of10% palladium-charcoal catalyst (0.6 g.) in water (50 ml.) containing 2N-hydrochloric acid (2.5 ml.). The mixture was shaken with hydrogen atatmospheric pressure and room temperature for 18 hrs., when the catalystwas removed by filtration and washed with water. Basification of theaqueous filtrate with sodium carbonate and extraction with ether gave(i)isoemetine as a pale froth, identical (infrared and paperchromatography) with an authentic sample. The hydrochloride,crystallised from methanol-ether had M.P. 254-6 C. (Found: C, 59.2; H,8.0; N, 4.4; Ci, 12.2.

C29H4QN2O4' requires C, 59.1; H, 8.2; N, 4.75; Cl, 12.0%.)

EXAMPLE 10 Preparation of (i)emetine Catalytic hydrogenation of(i)N-benzyle-metine (0.29 g.) with 10% palladium-charcoal catalyst indilute hydrochloric acid solution, and isolation of the product as abovegave (:)emetine, isolated as the hydrobromide (0.12 g.), M.P. 228-232 C.(d.), (Found: C, 50.1; H, N, BI, C29H4004N22HBI'3H20 requires C, 50.0;H, 6.95; N, 4.0; Br, 22.9%.)

The infrared spectrum (bromoform) and R value of this product wereidentical with those of the hydrobromide of natural emetine.

12 We claim: 1. A process for the production of a compound of theformula where R is lower alkoxy and R is lower alkyl in which a compoundof the formula R q R N\ O-R ll "where R is lower alkoxy and R is loweralkyl.

3. N-benzyl emetine.

References Cited by the Examiner UNITED STATES PATENTS 3,121,720 2/1964Barton et a1. 260288 3,121,722 2/1964 Ritchie etal 260288 NICHOLAS s.RIZZO, Primary Examiner,

IRVING MARCUS, DON M. KERR, DONALD G.

DAUS, Examiners.

1. A PROCESS FOR THE PRODUCTION OF A COMPOUND OF THE FORMULA
 3. N-BENZYLEMETINE.